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Updated: Aug 13, 2026

Generation of Human Chimeric Antigen Receptor Regulatory T Cells
10:29

Generation of Human Chimeric Antigen Receptor Regulatory T Cells

Published on: January 3, 2025

Receptor-tethered orthogonal IL-2 enhances regulatory T cell therapy

Alyssa C Indart1,2, Huiyun Lyu1,2, Vinh Q Nguyen1

  • 1Diabetes Center, University of California, San Francisco , San Francisco, CA, USA.

The Journal of Experimental Medicine
|August 12, 2026
PubMed

Regulatory T cell (Treg) therapy is an emerging platform for controlling immune overactivation. Persistence of infused Tregs is limited by insufficient IL-2, which is essential for Treg survival and function. IL-2 activates many immune cells, imposing a challenge for the selective provision of IL-2 to infused Tregs. In this study, we found that infusions of orthogonal (ortho) IL-2 failed to enhance Tregs expressing a corresponding orthoIL-2 receptor (IL-2R) in a mouse model of autoimmune diabetes. Engineering Tregs with an orthoIL-2 tethered to its receptor achieved selective autocrine signaling; increased CD25, CTLA-4, and Foxp3 expression; supported Treg persistence without exogenous IL-2 in vivo; and improved the efficacy of Treg prevention of autoimmune diabetes. Inserting the tethered orthoIL-2 construct into the Foxp3 locus enabled Treg-specific self-reinforced expression through the activation of the Foxp3 locus by increased IL-2 signaling. Together, these results illustrate a safe and effective cell-engineering solution for overcoming Tregs' dependency on exogenous IL-2, thereby achieving superior therapeutic efficacy.

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